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Results for “Models, Genetic”

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PubMed1983

Sexual selection and fertility.

Genetic models are analyzed in which sexual selection is combined with fertility selection. In these models, the sexual selection acts on males, the fertility selection on either males, females or both sexes. The phenotypes thus selected may be determined either by dominant and recessive alleles or by each homozygous and heterozygous genotype. Polymorphisms of dominant and recessive phenotypes can be maintained in equilibrium by a balance between sexual and fertility selection. Generally fertility selection has a greater effect than viability selection in determining the point of equilibrium. The dominant phenotype is maintained at a lower frequency when at a fertility disadvantage than when at a viability disadvantage. When about 20% or more of the females mate preferentially, the models show that equilibria will be established at very different frequencies depending on whether fertility selection acts on males, females or both sexes. These results, applied to data of preferential mating of melanic two-spot ladybirds, predict differences in fertility which can be use to test the models. Symmetric models of preferences for each genotype also give rise to polymorphisms if the heterozygotes obtain an overall advantage.

Animals↗

PubMed1992

The relationship between cone pigments and behavioural sensitivity in a New World monkey (Callithrix jacchus jacchus).

Microspectrophotometric measurements of visual pigments and behavioural measurements of spectral sensitivity are reported for individual marmosets from 3 family groups. The sex differences and polymorphism that characterise the long-wave cone pigments in this species are well reflected by variations in the behavioural sensitivities. With one exception, the pattern of inheritance is compatible with a genetic model in which the long-wave pigment is specified by a single polymorphic locus on the X-chromosome. Measurements are also reported for the spectral absorbance of the marmoset lens, and these are used to reconstruct short-wave behavioural sensitivity from the microspectrophotometric measurements of the short-wave cones.

Animals↗

PubMed1982

Response of murine epidermis to 2,3,7,8-tetrachlorodibenzo-p-dioxin: interaction of the ah and hr loci.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatic hydrocarbons produce epidermal hyperplasia, hyperkeratosis and sebaceous gland metaplasia in the skin of mice bearing the recessive mutation (hr/hr) hairless. This response is mediated through the cytosol receptor protein: the structure-activity relationship for receptor binding corresponds to that for production of the skin lesion, and these histopathological changes segregate with the genetic polymorphism at the Ah locus, the locus determining the cytosol receptor. In HRS/J mice, an inbred strain segregating for the hr locus, both hairless (hr/hr) and haired (hr/+) mice possess the high-affinity cytosol receptor and respond to TCDD with the induction of epidermal aryl hydrocarbon hydroxylase activity, a receptor-mediated biochemical response; however, only hr/hr mice develop the proliferative/metaplastic skin response. We propose a genetic model for the interaction of the Ah and hr loci, to account for the differential response to TCDD observed in the skin of HRS/J hr/hr and hr/+ mice.

Animals↗

PubMed1995

Effects of access to a running wheel on food, water and ethanol intake in rats bred to accept ethanol.

Rats from the University of Indiana lines bred to accept ethanol (P rats) and not to accept ethanol (NP rats) were divided into two groups of 3 rats per group. The first group of P and NP rats was given free access to food, water and 5% (w/v) ethanol 24 h a day. After food, water and ethanol intake stabilized, a running wheel was introduced into the cage. Access to the running wheel decreased ethanol intake and increased water intake in P rats. When the running wheel was locked in place, ethanol intake by P rats increased, but when the wheel was unlocked again, no decrease in ethanol intake occurred. Access to the running wheel did not affect food, water or ethanol intake in NP rats. The decrease in ethanol intake when the running wheel was introduced was replicated in the second group of P rats exposed to 5% ethanol and later to 10% ethanol. The decreases in ethanol consumption produced by the introduction of a running wheel for this genetic model of alcohol consumption are similar to those previously reported using schedule-induced polydipsia to induce ethanol intake.

Alcohol Drinking↗

PubMed2004

Nifedipine affects the anticonvulsant activity of topiramate in various animal models of epilepsy.

Topiramate (TPM), a new generation antiepileptic drug was investigated for its anticonvulsant effects in various models of genetically determined and chemically induced epilepsy in rodents. In addition, based on recent electrophysiological data suggesting that TPM may interact with L-type Ca(2+) channels, we evaluated the effects of a concomitant administration of L-type Ca(2+) channel modulators on TPM's antiepileptic properties. TPM, dose-dependently, protected against audiogenic seizures in DBA/2 mice. Concomitant treatment with TPM and a low dose of L-type Ca(2+) channel antagonists nifedipine or verapamil or with the L-type Ca(2+) channel agonist, S(-)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3-pyridinecarboxylic acid methyl ester (Bay k 8644) was able to increase the ED(50) for this drug. TPM also protected against seizures induced by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), 4-aminopyridine (4-AP) and pentylenetetrazole (PTZ), but this activity was not significantly modified by nifedipine. TPM, dose-dependently, reduced the number and duration of epileptic spike-wave discharges (SWDs) both in WAG/Rij rats and lethargic (lh/lh) mice, two genetic models of absence epilepsy. Nifedipine decreased TPM's activity in WAG/Rij rats but paradoxically enhanced it in lh/lh mice, whereas Bay k 8644 displayed opposite effects in both absence models. These results confirm TPM's broad spectrum of anticonvulsant activity and support the proposal that a modulation of neuronal L-type Ca(2+) channel activity plays an important role in its antiepileptic activity.

Animals↗

PubMed2006

Effects of genetically altered brain glucocorticoid receptor action on behavior and adrenal axis regulation in mice.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with vulnerability to a number of psychiatric diseases including major depression, bipolar disorder, anxiety disorders, and schizophrenia. The HPA axis is activated in response to stress and in a characteristic circadian rhythm, resulting in the release of glucocorticoid hormones from the adrenal cortex. These hormones act on peripheral target tissues to restore homeostasis to the organism and engage glucocorticoid receptors (GR) in the CNS to control the intensity and duration of the stress response. Alterations in this glucocorticoid sensing system may underlie the HPA axis changes associated with psychiatric disorders. Recently, a number of lines of mice with genetically altered GR signaling in the CNS have been generated to address this hypothesis. Here, we summarize findings from new genetic models that indicate a critical role for GR signaling in the CNS in normal regulation of the HPA axis and behavioral/emotional stability.

Animals↗

PubMed1995

Familial sinistrality: the utility of calculating exact genotype probabilities for individuals.

Measures of familial sinistrality are frequently used in neuropsychological research. However they suffer from the problem that they are essentially a global measure of phenotypes in the family, whereas they are interpreted as an indicator of the genotype of the individual concerned. In this paper it is shown how to calculate a precise probabilistic estimate of a proband's genotype, given a particular genetic model of handedness, using all of the information available in a family tree. Example calculations are provided for a range of families with one or two sinistral relatives. Genotype probabilities are also calculated for a large population data set (the National Childhood Encephalopathy Study) and it is shown that familial sinistrality does not account for all of the variability present in the genotype probabilities, and that genotype probabilities provide an additional prediction of individual sinistrality after taking familial sinistrality into account, whereas all of the information in familial sinistrality is accounted for by the genotype probabilities. Finally it is shown how genotype probabilities can be used to assess whether there is heterozygote advantage for a characteristic, and using this method it is suggested that there is no support for heterozygotes having higher intellectual ability than homozygotes.

Family↗

PubMed1991

Levels of selection, evolution of sex in RNA viruses, and the origin of life.

Multi-component RNA viruses have genomes that are segmented into two or more RNA molecules. A viral particle carries only one RNA molecule. Reproduction of a particle requires complementation by particles carrying other segments of the genome. Complementation is achieved when a group of particles co-infects the same host cell and forms a co-infection group. I have previously proposed the hypothesis that multi-component reproduction evolved in RNA viruses as a form of sex. Multi-component viruses may need sex because, like all RNA viruses, they have very high mutation rates. On the other hand, Nee (1987, J. molec. Biol. 25, 277-281.) has proposed the hypothesis that multi-component genomes evolved because smaller RNA molecules are favored by selection on RNAs within a host cell. Nee (1989, J. theor. Biol. 138, 407-412.) also claimed that selection on RNAs alone can account for the evolution of multi-component viruses. He criticized the viral sex hypothesis because, in his view, co-infection groups are not units of selection and are too transient to be engaged in sex. These two hypotheses were further examined through population genetic models. Three evolutionary agents are assumed to operate in the models. Selection on co-infection groups favors retention of the genome on one large RNA molecule because larger RNAs require less complementation. Selection on RNAs favor segmentation of the viral genome into smaller RNAs, which are replicated and encapsidated more rapidly. Mutation pressure also favors smaller molecules because those molecules are smaller targets for deleterious mutations. Analysis of the models shows that (when parameter values argued to be biologically realistic are used) selection on co-infection groups is necessary for the evolutionary persistence of multi-component viruses. Without selection on co-infections groups to oppose mutation pressure and selection on RNAs, a population of multi-component viruses is displaced by a population of parasitic viral RNAs that are replication and encapsidation specialists. These results support arguments that co-infection groups are units of selection in multi-component viruses. Both mutation pressure and selection on RNAs may be responsible for the evolution of genome segmentation in multi-component viruses because there is good evidence documenting the action of both in RNA viruses.(ABSTRACT TRUNCATED AT 400 WORDS)

Biological Evolution↗

PubMed1992

Kin selection in density regulated populations.

The process of kin selection has both intra- and inter-group components (Hamilton, 1975, in: Biosocial Anthropology Wade, 1980). Group advantageous characteristics can evolve when inter-group differences in fertility are sufficiently great to overcome any within-group disadvantage of the trait. The potential magnitude of inter-group differences in fertility is determined largely by the way a population is regulated. Inter-group differences decrease as the spatial scale over which a population is regulated becomes increasingly localized. The present paper extends previous work by Boyd (1982, Anim. Behav. 30, 972-982) on the quantitative relation between kin selection and density regulation. A simple genetic model is employed to examine the conditions under which the interaction of local density regulation and kin selection can maintain a stable polymorphism. The ecological factors determining the spatial and temporal scale of density regulation are discussed. Finally, the results are applied to two biological cases in which local density regulation may be influencing the direction of phenotypic plasticity in group advantageous characters.

Animals↗

PubMed1992

Female infanticide and human sex ratio evolution.

The possible effect on the evolution of the human sex ratio of a preference for male children is examined in a genetic model. It is shown that the killing of infant daughters can lead to either a female- or a male-biased sex ratio, the outcome depending on the decision rule used to determine the fate of a child. This reconciles long-standing contradictory results.

Biological Evolution↗

PubMed1987

The impact of symbolism on immunogenetics: an application to HLA.

The genes coding for the class I human lymphocyte antigens (HLA) are located on chromosome 6. These antigens are involved with the immunological interaction between cells. In some immunogenetic systems, such as HLA in humans, genes are defined by antibody/antigen reaction and are denoted by single symbolic identifiers. This symbolization assumes a one-to-one correspondence between antibodies, antigens and genes. Recent molecular studies, however, suggest that HLA antibody/antigen reaction is complex and most HLA class I specific antibodies may not uniquely identify a single allelic product. Where cross-reactivity is present in an immunogenetic system it is important to label each reagent with symbols corresponding to all genes coding for antigens with which the reagent will react. The problems of cross-reactive groups and unexplained linkage relations may be elucidated by the redefinition and clarification of certain HLA antigens. A computer program can suggest such labelling schemes using input given by phenotype reaction patterns with a panel of reagents. When this program was applied to data on the class I HLA antigens a genetic model was suggested that differs somewhat from the currently accepted model. The new model is able to predict what would appear as linkage relations in the accepted model. Our methodology can provide alternate models to guide in typing cloned genes in terms of the HLA locus and alleles.

Chromosome Mapping↗

PubMed1988

Evolution of sex in RNA viruses.

The distribution of deleterious mutations in a population of organisms is determined by the opposing effects of two forces, mutation pressure and selection. If mutation rates are high, the resulting mutation-selection balance can generate a substantial mutational load in the population. Sex can be advantageous to organisms experiencing high mutation rates because it can either buffer the mutation-selection balance from genetic drift, thus preventing any increases in the mutational load (Muller, 1964: Mut. Res. 1, 2), or decrease the mutational load by increasing the efficiency of selection (Crow, 1970: Biomathematics 1, 128). Muller's hypothesis assumes that deleterious mutations act independently, whereas Crow's hypothesis assumes that deleterious mutations interact synergistically, i.e., the acquisition of a deleterious mutation is proportionately more harmful to a genome with many mutations than it is to a genome with a few mutations. RNA viruses provide a test for these two hypotheses because they have extremely high mutation rates and appear to have evolved specific adaptations to reproduce sexually. Population genetic models for RNA viruses show that Muller's and Crow's hypotheses are also possible explanations for why sex is advantageous to these viruses. A re-analysis of published data on RNA viruses that are cultured by undiluted passage suggests that deleterious mutations in such viruses interact synergistically and that sex evolved there as a mechanism to reduce the mutational load.

Models, Genetic↗

PubMed2002

Genetic aspects of Labrador Retriever myopathy.

Labrador Retriever myopathy (LRM) has become a relatively common muscular disease. The objective of our prospective study was to determine by segregation analyses a plausible mode of inheritance within a Labrador Retriever population. Therefore we performed neurological examinations, as well as electromyographic and histopathological evaluations of 58 closely related dogs. Seven dogs with an average age of 27.8 months had clinical signs consistent with LRM including exercise intolerance or fatigue. The diagnosis was based on neurological deficits and confirmed by histopathological results of muscle biopsy. We found in all cases obvious differences in fiber calibre size associated with texture disturbances. In addition, we found 41 clinically normal dogs with histological findings consistent with LRM. Three genetic models, the major gene, the mixed inheritance as well as the environmental model, were evaluated by segregation analyses. They were applied to an extended pedigree including 164 non-randomly ascertained related Labradors. According to phenotype the clinically examined dogs were divided into two different data sets. One data set distinguished between clinically normal and abnormal dogs, the second data set between histopathologically normal and abnormal dogs. We concluded that the clinical form of LRM is transmitted by a major gene and controlled by an autosomal recessive mode of inheritance. Furthermore, for expression of the subclinical form an additional gene or an environmental factor is responsible. Our findings suggest that LRM is similar to limb-girdle muscular dystrophy in man and therefore, may be used in the future as an animal model.

Animals↗

PubMed2000

Sensitivity and tolerance to ethanol in mouse lines selected for ethanol-induced hypothermia.

Within-family selective breeding techniques have been used to create two lines of mice to be insensitive (HOT) and two lines to be sensitive (COLD) to the hypothermic effects of an acute 3.0-g/kg ethanol (EtOH) injection. Previous studies have found HOT mice to be relatively resistant to the development of tolerance to this effect, whereas COLD mice readily develop tolerance. The breeding program is currently in selected Generation 52, and the HOT and COLD mice differ by about 10 degrees C (average of both replicates) in their selected hypothermic response. Starting with selection Generation 20, separate lines of mice were inbred from the HOT-2 and COLD-2 selected lines, while selection continued for the original two replicate lines of HOT and COLD mice. To assess whether different dose treatments would produce differential tolerance development in the HOT and COLD selected lines, we administered different dose regimens across 5 days to HOT and COLD mice. The COLD mice developed tolerance while the HOT mice did not, regardless of total EtOH administered. In a separate study, we administered EtOH (3.0 g/kg) to mice for 3 days to assess a shorter tolerance paradigm. We also present here responses to the selection dose of 3.0-g/kg EtOH in the inbred HOT (IHOT-2) and COLD (ICOLD-2) mice tested after 41 generations of brother-sister mating. In addition, we report recent attempts to find doses of EtOH that would produce an equivalent initial hypothermic response in each of the six lines (HOT-1, COLD-1, HOT-2, COLD-2, ICOLD-2, and IHOT-2). When doses were selected to produce similar initial hypothermic sensitivity, tolerance was tested by giving three daily doses and examining the attenuation of the hypothermic response on the third day. All three COLD lines developed significant tolerance, while the HOT lines did not. The HOT and COLD mice provide a genetic model to study mechanisms mediating acute EtOH-induced hypothermia as well as tolerance development.

Animals↗

PubMed2003

Tube morphogenesis: making and shaping biological tubes.

Many organs are composed of epithelial tubes that transport vital fluids. Such tubular organs develop in many different ways and generate tubes of widely varying sizes and structures, but always with the apical epithelial surface lining the lumen. We describe recent progress in several diverse cell culture and genetic models of tube morphogenesis, which suggest apical membrane biogenesis, vesicle fusion, and secretion play central roles in tube formation and growth. We propose a unifying mechanism of tube morphogenesis that has been modified to create tube diversity and describe how defects in the tube size-sensing step can lead to polycystic kidney disease.

Animals↗

PubMed2000

A calcium-inhibited Drosophila adenylyl cyclase.

Mammals possess a family of transmembrane, G-protein-responsive adenylyl cyclase isoforms (tmACs) encoded by distinct genes differing in their patterns of expression and modes of biochemical regulation. Our previous work confirmed that Drosophila melanogaster also possesses a family of tmAC isoforms defining the fly as a suitable genetic model for discerning mammalian tmAC function. We now describe a Drosophila tmAC, DAC39E, which employs a novel means for regulating its expression; differential exon utilization results in a developmental switch in DAC39E protein. DAC39E protein sequence is most closely related to mammalian type III AC, and it is predominantly expressed in the central nervous system (CNS) and olfactory organs, suggesting a role in processing sensory signaling inputs. DAC39E catalytic activity is inhibited by micromolar concentrations of calcium; therefore, DAC39E is oppositely regulated by calcium compared to the only other tmAC shown to be expressed in the Drosophila CNS, Rutabaga AC. The presence of both positively and negatively regulated tmACs suggests a complex mode of cross-talk between cAMP and calcium signal transduction pathways in the fly CNS.

Adenylyl Cyclase Inhibitors↗

PubMed2003

Serotonergic dorsal raphe neurons from obese zucker rats are hyperexcitable.

Release of serotonin (5-HT) from dorsal raphe nucleus (DRN) neurons projecting to the ventromedial hypothalamus (VMH) has a modulatory effect on the neural pathway involved in feeding, hunger, and satiety. The obese Zucker rat, an animal model of genetic obesity, exhibits differences in serotonin signaling as well as a mutated leptin receptor. To evaluate possible mechanisms underlying this difference in serotonin signaling, we have compared electrophysiological responses of DRN neurons from 14- to 25-day-old male lean (Fa/Fa) and obese (fa/fa) Zucker rats using the whole-cell patch clamp technique on cells in brain slices from these animals. We found that the resting properties of these neurons are not different, but the DRN neurons from obese rats are hyperexcitable in response to current injection. This hyperexcitability is not accompanied by an increase in the depolarization caused by current injection or by changes in the threshold for spiking. However, the hyperexcitability is accompanied by reduction in the size and time course of the afterhyperpolarization (AHP) following an action potential. DRN neurons of obese rats recover from the AHP faster due to a smaller amplitude AHP and a faster time constant (tau) of decay of the AHP. These deficits are not due to changes in the spike waveform, as the spike amplitude and duration do not differ between lean and obese animals. In summary, we provide evidence that serotonergic DRN neurons from obese Zucker rats are intrinsically hyperexcitable compared with those from lean rats. These results suggest a potential mechanism for the reported increase in 5-HT release at the VMH of obese rats during feeding, and provide the first direct evidence of changes in the intrinsic activity of serotonergic neurons, which are crucial regulators of feeding behavior, in a genetic model of obesity.

Action Potentials↗

PubMed2001

Plant salt tolerance.

Soil salinity is a major abiotic stress in plant agriculture worldwide. This has led to research into salt tolerance with the aim of improving crop plants. However, salt tolerance might have much wider implications because transgenic salt-tolerant plants often also tolerate other stresses including chilling, freezing, heat and drought. Unfortunately, suitable genetic model systems have been hard to find. A recently discovered halophytic plant species, Thellungiella halophila, now promises to help in the detection of new tolerance determinants and operating pathways in a model system that is not limited to Arabidopsis traits or ecotype variations.

Adaptation, Physiological↗